The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers

Hamada A Mokhlis; Recep Bayraktar; Nashwa N Kabil; Ayse Caner; Nermin Kahraman; Cristian Rodriguez-Aguayo; Erika P Zambalde; Jianting Sheng; Kübra Karagoz; Pinar Kanlikilicer; Abdel Aziz H Abdel Aziz; Tamer M Abdelghany; Ahmed A Ashour; Stephen Wong; Michael L Gatza; George A Calin; Gabriel Lopez-Berestein; Bulent Ozpolat

doi:10.1016/j.omtn.2018.11.019

The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers

Mol Ther Nucleic Acids. 2019 Mar 1:14:301-317. doi: 10.1016/j.omtn.2018.11.019. Epub 2018 Dec 13.

Authors

Hamada A Mokhlis¹, Recep Bayraktar², Nashwa N Kabil², Ayse Caner², Nermin Kahraman², Cristian Rodriguez-Aguayo², Erika P Zambalde², Jianting Sheng³, Kübra Karagoz⁴, Pinar Kanlikilicer², Abdel Aziz H Abdel Aziz⁵, Tamer M Abdelghany⁵, Ahmed A Ashour⁵, Stephen Wong³, Michael L Gatza⁴, George A Calin⁶, Gabriel Lopez-Berestein⁶, Bulent Ozpolat⁷

Affiliations

¹ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, The University of Al-Azhar, Cairo, Egypt.
² Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Systems Medicine & Bioengineering, Houston Methodist Institute for Academic Medicine Research Institute, Houston Methodist Weill Cornell Medical College, Houston, TX, USA.
⁴ Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
⁵ Department of Pharmacology and Toxicology, Faculty of Pharmacy, The University of Al-Azhar, Cairo, Egypt.
⁶ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: bozpolat@mdanderson.org.

Abstract

KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3' UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.

Keywords: KRAS; breast cancer; gene regulation; gene silencing; invasion; liposomes; miR-873; microRNA; nanoparticles; ncRNA; non-coding RNA; oncogene; pancreatic cancer; proliferation; therapy; triple-negative breast cancer; tumorigenesis.

Abstract

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